Congestive heart failure is a complex disease involving multiple genetic and environmental factors. Three years ago, the laboratories of Dr. Yibin Wang, a molecular biologist with expertise in heart failure, and Dr. Aldons Lusis, a geneticist working in the area of cardiovascular disease, joined forces to perform a genetic screen in a hybrid mouse diversity panel (HMDP) to identify genes contributing to common forms of heart failure. For the past two years, this work has been supported by a multi- PI R21. This support enabled us to complete the preliminary screen and identified over 30 genome-wide significant loci harboring genes contributing to different aspects of cardiac pathologies induced by chronic stimulation of the -adrenergic agonist isoproterenol (ISO), including hypertrophy, fibrosis, and cardiac dysfunction and remodeling. Moreover, gene expression profiles were obtained from all HMDP mouse hearts in control mice and following ISO treatment. These rich datasets containing genetic information detailed cardiac phenotype parameters and comprehensive cardiac transcriptome profiles from 107 inbred strains of mice will allow us to harness the power of genetics and systems approaches to identify novel molecular pathways contributing to the specific aspects of cardiac pathology during heart failure. Indeed, we observed a dramatic diversity of heart failure phenotypes among all HMDP strains following ISO stimulation and discovered a number of genetic loci and gene modules with significant association with cardiac hypertrophy and fibrosis. These data support the overall hypothesis that common genetic variants have a major contribution to the pathogenesis of heart failure. Uncovering the mechanistic basis of these newly discovered HF associated genes and their interactions via systems approach is the overarching goal of this proposal. Specifically, in Aim 1, we will extend our systems studies to discover genes and gene modules significantly associated with cardiac pathology induced by chronic angiotensin II treatment (AngII). We will identify unique and common genes involved in AR vs. AR-specific pathogenesis in heart. In Aim 2, we will investigate the molecular mechanisms underlying a candidate gene associated with heart failure, Miat, that encodes a long-non-coding (lnc)RNA with a previously unknown function in heart. In Aim 3, we will investigate the mechanism and functional role of Abcc6, a GWAS candidate gene, in stress induced cardiac fibrosis. These studies will reveal the underlying genetic contributions to specific features of heart failure, and the uncovered novel pathology associated genes and their interaction should provide new insights to the mechanism of the disease.